Allosteric site prediction and transmission of functional residues with atomistic graph analysis

变构作为“生命的第二秘密”，通过分子间的远距离结合来调节蛋白质的活性，近年来受到越来越多的关注，变构调节的普遍性和变构药物的巨大优势使得对变构机制的理解具有重要价值，但目前还缺乏有效预测变构位点的计算方法。键对键（B2B）倾向分析已经成功地确定了一组不同的蛋白质的变构位点，而仅仅是使用原子能量加权蛋白质图的正构位点/配体的知识，并且优于迄今为止的其他方法。然而，并非所有蛋白质都具有明确定义的正构位点，这限制了它们作为药物靶标的潜力，并使B2B倾向分析不太有效。在过去的二十年中，蛋白质靶点的共价抑制重新流行，并揭示了含有固有反应性氨基酸的变构位点，主要是半胱氨酸，但包括赖氨酸，组氨酸和苏氨酸。5靶向非催化半胱氨酸引起了化学生物学家的越来越多的关注6，7与化学蛋白质组学技术开发，以挖掘化学可接近的半胱氨酸8，因此，在不知道正构位点的情况下预测含有/接近反应性氨基酸的变构位点将提高共价药物发现过程中的成本和时间效率。这个博士学位的重点是发展原子图分析方法，可以识别功能的变构残基和它们的变构传递路径。

Allostery, the 'second secret of life', that regulates protein activity through molecular binding at a distant site from the orthosteric site, has drawn increasing attention.The universality of allosteric regulation and the great benefits of allosteric drugs make understanding allosteric mechanisms invaluable, yet there are few computational methods to effectively predict allosteric sites. Bond-to-bond (B2B) propensity analysis has successfully identified allosteric sites for a diverse group of proteins with merely the knowledge of the orthosteric sites/ligands using the atomistic energy-weighted protein graphs and outperformed other methods to date.3,4 Crucially, it remains computationally efficient as it scales almost linearly. However, not all proteins possess clearly defined orthosteric sites which limits their potential as drug targets and renders B2B propensity analysis less effective. Covalent inhibition of protein targets regained popularity over the past two decades and reveal allosteric sites containing inherently reactive amino acids, primarily cysteines, but including lysine, histidine and threonine.5 Targeting non-catalytic cysteines has drawn increased attention from chemical biologists6,7 with chemoproteomic technologies developed to mine chemically accessible cysteines8,9 but limited experimental methods to discern functional cysteines.10,11 Therefore, predicting allosteric sites containing/in proximation to reactive amino acids without the knowledge of the orthosteric sites would enhance cost and time efficiency in the covalent drug discovery process. This PhD focuses on developing atomistic graph anlaysis methods that can identify functional allosteric residues and their paths of allosteric transmission.